The aryl hydrocarbon receptor and interferon gamma generate antiviral states via transcriptional repression

Kueck, Tonya; Cassella, Elena; Holler, Jessica; Kim, Baek; Bieniasz, Paul D.

doi:10.7554/elife.38867

Cited by 31 publications

(32 citation statements)

References 71 publications

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“…As mentioned above, AhR functions in a proviral manner in IAV infection by inducing TiPARP (40). In contrast, AhR activation in HSV-or HIV-infected macrophages restricts replication by inhibiting expression of cyclins and cyclin-dependent kinases (39). Thus, AhR activation during viral infection has differing effects and modulates multiple cellular pathways, many of which remain uncharacterized.…”

Section: Mhv-a59 Infection Induces Tiparp Expression Through Ifn-i-dementioning

confidence: 99%

“…In contrast, less is known about the role of AhR during virus infection. While previous work has explored pathways affected by AhR activation during influenza A virus (IAV), herpes simplex virus (HSV), hepatitis C virus (HCV), and Epstein-Barr virus (EBV) infection (38)(39)(40)(41), the virological impact of AhR is still largely uncharacterized. Here, we show that CoV replication in macrophages results in AhR activation in an IDO1-independent manner, leading to increased expression of several downstream effectors and to modulation of the cytokine response.…”

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confidence: 99%

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Murine Coronavirus Infection Activates the Aryl Hydrocarbon Receptor in an Indoleamine 2,3-Dioxygenase-Independent Manner, Contributing to Cytokine Modulation and Proviral TCDD-Inducible-PARP Expression

Grunewald

Shaban

Mackin

et al. 2020

J Virol

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The aryl hydrocarbon receptor (AhR) is a cytoplasmic receptor/transcription factor that modulates several cellular and immunological processes following activation by pathogen-associated stimuli, though its role during virus infection is largely unknown. Here, we show that AhR is activated in cells infected with mouse hepatitis virus (MHV), a coronavirus (CoV), and contributes to the upregulation of downstream effector TCDD-inducible poly(ADP-ribose) polymerase (TiPARP) during infection. Knockdown of TiPARP reduced viral replication and increased interferon expression, suggesting that TiPARP functions in a proviral manner during MHV infection. We also show that MHV replication induced the expression of other genes known to be downstream of AhR in macrophages and dendritic cells and in livers of infected mice. Further, we found that chemically inhibiting or activating AhR reciprocally modulated the expression levels of cytokines induced by infection, specifically, interleukin 1␤ (IL-1␤), IL-10, and tumor necrosis factor alpha (TNF-␣), consistent with a role for AhR activation in the host response to MHV infection. Furthermore, while indoleamine 2,3-dioxygenase (IDO1) drives AhR activation in other settings, MHV infection induced equal expression of downstream genes in wild-type (WT) and IDO1 Ϫ/Ϫ macrophages, suggesting an alternative pathway of AhR activation. In summary, we show that coronaviruses elicit AhR activation by an IDO1-independent pathway, contributing to upregulation of downstream effectors, including the proviral factor TiPARP, and to modulation of cytokine gene expression, and we identify a previously unappreciated role for AhR signaling in CoV pathogenesis. IMPORTANCE Coronaviruses are a family of positive-sense RNA viruses with human and agricultural significance. Characterizing the mechanisms by which coronavirus infection dictates pathogenesis or counters the host immune response would provide targets for the development of therapeutics. Here, we show that the aryl hydrocarbon receptor (AhR) is activated in cells infected with a prototypic coronavirus, mouse hepatitis virus (MHV), resulting in the expression of several effector genes. AhR is important for modulation of the host immune response to MHV and plays a role in the expression of TiPARP, which we show is required for maximal viral replication. Taken together, our findings highlight a previously unidentified role for AhR in regulating coronavirus replication and the immune response to the virus.

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Section: Mhv-a59 Infection Induces Tiparp Expression Through Ifn-i-dementioning

confidence: 99%

mentioning

confidence: 99%

Murine Coronavirus Infection Activates the Aryl Hydrocarbon Receptor in an Indoleamine 2,3-Dioxygenase-Independent Manner, Contributing to Cytokine Modulation and Proviral TCDD-Inducible-PARP Expression

Grunewald

Shaban

Mackin

et al. 2020

J Virol

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“…However, IFNγ also stimulates a non-canonical signal transactivation [38] like the activation of the IFN-stimulated gene factor 3 (ISGF3) composed of STAT1, STAT2, and IRF9 [39,40,41,42,43,44]. Recently, it has become evident that IFNγ also represses the expression of numerous genes termed IFN-repressed genes (IRepGs) [43,45,46]. In combination, the IFN-induced alterations of ISGs and IRepGs elicit antiviral activity [45,46].…”

Section: Interferonsmentioning

confidence: 99%

Cellular Cullin RING Ubiquitin Ligases: Druggable Host Dependency Factors of Cytomegaloviruses

Becker

Le‐Trilling

Trilling

2019

IJMS

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Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus that frequently causes morbidity and mortality in individuals with insufficient immunity, such as transplant recipients, AIDS patients, and congenitally infected newborns. Several antiviral drugs are approved to treat HCMV infections. However, resistant HCMV mutants can arise in patients receiving long-term therapy. Additionally, side effects and the risk to cause birth defects limit the use of currently approved antivirals against HCMV. Therefore, the identification of new drug targets is of clinical relevance. Recent work identified DNA-damage binding protein 1 (DDB1) and the family of the cellular cullin (Cul) RING ubiquitin (Ub) ligases (CRLs) as host-derived factors that are relevant for the replication of human and mouse cytomegaloviruses. The first-in-class CRL inhibitory compound Pevonedistat (also called MLN4924) is currently under investigation as an anti-tumor drug in several clinical trials. Cytomegaloviruses exploit CRLs to regulate the abundance of viral proteins, and to induce the proteasomal degradation of host restriction factors involved in innate and intrinsic immunity. Accordingly, pharmacological blockade of CRL activity diminishes viral replication in cell culture. In this review, we summarize the current knowledge concerning the relevance of DDB1 and CRLs during cytomegalovirus replication and discuss chances and drawbacks of CRL inhibitory drugs as potential antiviral treatment against HCMV.

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“…All ILC3 express high levels of aryl hydrocarbon receptor (AhR), another ligand‐controlled transcription factor, which can sense dietary, bacterial and endogenous (tryptophan‐derived) ligands . AhR is broadly expressed throughout the cellular components of the immune system, including its lymphoid and myeloid branches . AhR is expressed by all ILC subsets and NK cells, but NKp46 − CD4 − ILC3 display particularly high levels of expression .…”

Section: Ilc3 Translate Nutrient‐derived Signals Into Lymphoid Organmentioning

confidence: 99%

Innate lymphoid cells, mediators of tissue homeostasis, adaptation and disease tolerance

Branzk

Gronke

Diefenbach

2018

Immunological Reviews

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Summary Innate lymphoid cells (ILC) are a recently identified group of tissue‐resident innate lymphocytes. Available data support the view that ILC or their progenitors are deposited and retained in tissues early during ontogeny. Thereby, ILC become an integral cellular component of tissues and organs. Here, we will review the intriguing relationships between ILC and basic developmental and homeostatic processes within tissues. Studying ILC has already led to the appreciation of the integral roles of immune cells in tissue homeostasis, morphogenesis, metabolism, regeneration, and growth. This area of immunology has not yet been studied in‐depth but is likely to reveal important networks contributing to disease tolerance and may be harnessed for future therapeutic approaches.

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The aryl hydrocarbon receptor and interferon gamma generate antiviral states via transcriptional repression

Cited by 31 publications

References 71 publications

Murine Coronavirus Infection Activates the Aryl Hydrocarbon Receptor in an Indoleamine 2,3-Dioxygenase-Independent Manner, Contributing to Cytokine Modulation and Proviral TCDD-Inducible-PARP Expression

Murine Coronavirus Infection Activates the Aryl Hydrocarbon Receptor in an Indoleamine 2,3-Dioxygenase-Independent Manner, Contributing to Cytokine Modulation and Proviral TCDD-Inducible-PARP Expression

Cellular Cullin RING Ubiquitin Ligases: Druggable Host Dependency Factors of Cytomegaloviruses

Innate lymphoid cells, mediators of tissue homeostasis, adaptation and disease tolerance

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